1. Field of the Invention
This invention is drawn to a method of treating bone lesions and a composition comprised of a new combination of known substances which provide space filling, interfacial bonding of the ceramic and bone and the improved osteogenic, osteoinductive and osteoconductive properties of the organic substances placed with and onto the surfaces of the ceramic compounds. Specifically, the composition comprises an inorganic phase and organic phase wherein the inorganic phase comprises porous particulate tricalcium phosphate (hereinafter TCP) ceramic or a nonporous or microporous particulate hydroxylapatite (hereinafter HAP) ceramic or a mixture of porous particulate TCP ceramic and nonporous or microporous particulate HAP, wherein the organic phase comprises a purified hydrated collagen product which is mixed with and forms a continuous or substantially continuous surface coating over said inorganic phase and a hydrated collagen-demineralized bone product which is mixed with and forms a continuous or substantially continuous surface coating over said purified hydrated collagen product surface coating or the organic phase comprises a hydrated collagen-demineralized bone product which is mixed with and forms a continuous or substantially continuous surface coating over said inorganic phase and a purified hydrated collagen product which is mixed with and forms a continuous or substantially continuous surface coating over said hydrated collagen-demineralized bone product surface coating. The composition may be applied at surgical reconstruction or delivered to the lesion site by a syringe injection.
2. Description of the Prior Art
The medical community at large has utilized a large variety of metals, alloys, ceramics, carbons, polymers, tissue products and externally applied techniques such as electrical stimulation for the treatment of bone lesions. Metals and alloys have, for the most part, included iron, cobalt and titanium based systems. The ceramics include aluminum oxide, hydroxylapatites, calcium sulfates, zirconium oxides, calcium phosphates and other selected compounds. The carbons have been vitreous (polycrystalline glassy carbon) and the pyrolytic carbon-silicon compounds. The polymers, recently utilized, have emphasized the ultra-high molecular weight polyethylene, polysulfone, polytetrafluoroethylene, silicon rubbers, and polyesters.
The tissue product most often used for the treatment of bone lesions is autogenous bone surgically removed from the host and placed at the defect site. Both homologous and heterogeneous bone products for example, bovine bone morphogenetic protein (BMP), bovine inorganic bone, human bank bone, etc., are also used for selected treatments. Many hospitals and clinics now maintain bone bank (storage) facilities.
Numerous attempts have been made to replace the autogenous bone used in surgical procedures by inorganic biomaterials, artificial bone, metals, alloys and polymers, etc., especially in non-unions and major segmental defects. However, only limited success has been achieved.
The implantation of TCP rods in prepared segmental bone replacements and non-union correction resulted in scattered data and therefore unpredictable healing. Even where the TCP implant for non-union correction was accompanied by direct current electrical stimulation, only a very low probability for re-establishment of a bony union resulted. It was established, however, that porous TCP ceramic can serve as a scaffold with bone proliferation through the large interconnecting pores. Lemons, J. E., Response of Combined Electrical Stimulation and Biodegradable Ceramic, Annual Report 2, USAMRDS Contract DAMD17-75-C-5044, 1976.
A later study utilized autogenous bone and porous TCP ceramic rod, porous TCP rod or granular form TCP alone and a mixture of autogenous bone and granular porous TCP ceramic. This study indicated that the porous TCP rod alone for non-union correction was unacceptable as only two of twenty procedures obtained a bony union. The granular form alone showed incomplete healing at six weeks. The use of the rod form of porous TCP with autogenous bone was much better, with ten of twelve procedures establishing clinical union. The use of granular porous TCP ceramic and autogenous bone implant (50-50) showed clinical union at six weeks. Lemons, J. E., Response of Combined Electrical Stimulation and Biodegradable Ceramic, Annual Report 3, USAMRDS Contract DAMD17-85-C-5044, 1978.
In a 1979 study, the treatment of segmental eight mm lesions with granular porous TCP ceramic alone failed to heal after six weeks. However, when granular porous TCP ceramic was mixed with autogenous bone, some bridging occurred in six weeks. The best implant material was autogenous bone which showed good bridging in four weeks. When non-union correction was attempted, bridging occurred in only three of eight for the granular ceramic implant and only two of six for a 50/50 (ceramic-autogenous bone). Total autogenous bone showed a clinical union in six of seven procedures. Lemons, J. E., Response of Combined Electrical Stimulation and Biodegradable Ceramic, Annual Report 3, USAMRDS Contract DAMD17-85-C-5044, 1979.
In a 1981 study, healing of 23 of 25 eight mm tibial lesions, when implanted with granular (1, 2 or 3 mm average size) porous TCP ceramic mixed with equal weights of autogenous bone. However, the rod form and the granular form implants alone, while showing good biocompatability, failed to establish the same success. Lemons, J. E., Response of Combined Electrical Stimulation and Applied Laboratory and Clinical Studies on Biodegradable Ceramic, Annual Report, USAMRDS Contracts DAMD17-75-C5044 and DAMD17-79-C-9173, 1981.
In March 1982 a mixture comprising the granular form TCP (-40+100 mesh) and calcium hydroxylapatite (14 mesh) ceramic was mixed with autogenous bone and placed in a 8 mm length segmental rabbit tibial lesion. The mixture comprised equal amounts of TCP and hydroxylapatite and 50% autogenous bone. The tricalcium phosphate and hydroxylapatite granular form ceramics show good biocompatability. The hydroxylapatite is available from Sterling Winthrop Research Institute under the trademark "DURAPATITE". The combination of granular TCP ceramic and hydroxylapatite ceramic with 50% autogenous bone showed a healing of the 8 mm length segmental rabbit tibial lesion in 11 of the 12 procedures. Lemons, J. E., Applied Laboratory and Clinical Studies on Biodegradable Ceramic, USAMRDS Contract DAMD17-79-C-9173, 1982.
In a June 1982 study rod form porous TCP ceramic implanted at non-union sites, showed only 2 of 20 obtained a bony union. A combination of rod form porous TCP and autogeneous bone showed clinical union for 10 of 12 procedures. Electrical stimulation did not appear to greatly influence tissue ingrowth and biodegradation rates for porous TCP ceramics implants. Mixtures of autogeneous bone with granular from ceramic and autogeneous bone alone showed the best results with bridging at 6 weeks (50-50 mixture) and 4-6 weeks, respectively, of 8 mm length lesions. For total ceramic implants 14-16 weeks were required. In non-union lesions, mixtures of autogeneous bone and granular form TCP ceramic showed bridging for 2 of 6 (50-50 mixture), autogeneous bone alone, bridging for 6 of 7, and in ceramic alone, bridging for only 3 of 8. Lemons, J. E., Response of Combined Electrical Stimulation and Biodegradable Ceramics, Final Report USAMRDS Contract DAMD17-75-C- 5044, 1982.
In 1983 a new solid particulate TCP (-40,+100 mesh) was studied using 0.4 gram and 0.8 grams of TCP and 0.2/0.2 and 0.4/0.4 TCP and bone ratios within an 8 mm length rabbit tibial lesion. The TCP and autogenous bone mixture showed a slightly higher probability for clinical union compared to the TCP alone. Moreover, no statistically significant trends with respect to quantity or the presence of autogenous bone could be established.
Also in this study, the dog radii implants of TCP rod form illustrated that the results are quite variable for this type of an implant. The retained rod form showed wide range of interactions such as soft tissue reactions, fibrous incapsulations to normal bone and incorporation of the residual material. Lemons, J. E., Applied Laboratory and Clinical Studies on Biodegradable Ceramic, Annual Report, USAMRDS Contract DAMD17-79-C-9173, 1983.
U.S. Pat. No. 3,314,420 discloses an improved ceramic prosthetic part at least a portion of the surface area of the prosthetic part is porous to facilitate and to enable the growth of bone, muscle and fibrous tissue thereinto so as to incorporate said part into the muscular, skeletal system of the body into which the prosthetic part is implanted.
U.S. Pat. No. 3,713,860 teaches a bone substitute prepared by impregnating a porous aluminum oxide ceramic with pure methyl methacrylate monomer. The monomer is then polymerized by gama radiation. Portions of the polymer are then removed by a solution of a suitable solvent such as acetone in an ultrasonic bath where the muscle and bone attachment is desired. The finished product may then be sterilized by further radiation.
U.S. Pat. No. 3,767,437 teaches a new composition of matter for preparation of structures resembling cartilage and bone tissue with improved moisture resistant and water resistant properties. The new prosthetic structure is formed from a complex partial salt of collagen with a metal hydroxide and with an ionizable acid such as calcium hydroxide or phosphoric acid.
U.S. Pat. No. 3,892,649 discloses a method in which bone and organic matrix are simultaneously adhered by electro chemical deposition onto a metallic prosthesis. The coating of bone particles and organic binder onto the surface of the bone prosthesis is said to enhance bone growth on the prosthesis.
U.S. Pat. No. 3,919,723 teaches a prosthesis made of compacted aluminum oxide (Al.sub.2 O.sub.2) ceramic which has incorporated at or near the surface a substance such a apatite or apatite-like crystals which are capable of releasing bone-stimulating ionic material such as lithium ions, boron ions, fluoride ions, sodium ions, magnesium ions, silicon ions, phosphorous ions, potassium ions, calcium ions and mixtures thereof.
U.S. Pat. No. 3,949,073 teaches a method of augmenting connective tissue by administering a solution of solubilized, purified, native, in situ polymerizable collagen to the augmentation site. The implanted solution polymerizes at the site into a stable, non-reactive fibrous mass of tissue which is rapidly colonized by host cells and subsequently vascularized.
U.S. Pat. No. 4,051,598 teaches a porous dental implant with an osteogenic catalyst at the surface layer. The osteogenic catalysts are calcium carbonate, tricalcium phosphate, calcium fluoride, tribasic calcium phosphate, monobasic calcium phosphate, calcium glycero-phosphate, calcium lacticum, sodium fluoride, total bone substance, magnesium silicate, aluminum silicate, ascorbic acid, aluminum silicate, vitamin D, vitamin A, animal dentin, dibasic calcium phosphate, calcium glucosicum, calcium hexaphosphate, caoline, zinc oxide and mixtures thereof. The coated implant of this invention is said to overcome the bond failure between the implant and the surrounding tissue.
U.S. Pat. No. 4,052,754 teaches an implant that is, at least, partially composed of a biocompatible porous material which readily promotes the ingrowth of living tissue into the implant. A porous material of carbon fibers bonded to polytetrafluroethylene is disclosed as the preferred growth promoting material.
U.S. Pat. No. 4,164,794 disclosed a prosthesis at least a portion of which is covered by a porous coating of a bioengineering thermoplastic material such as polysulfones, polyphenylenesulfide, polyacetal, thermoplastic polyesters, polycarbonates, aromatic polyamides, aromatic polyamideimides, thermoplastic polyimides, polyarylketones, polyarylethylketones, polyarylethylnitriles and aromatic polyhydroxy ethers with specific physical characteristics as disclosed in the patent. The bioengineering thermoplastic coating promotes tissue ingrowth onto the prosthetic device.
U.S. Pat. No. 4,186,448 teaches the use of a biodegradable material which is prepared from known hydroxy acids such as polylactic acid.
U.S. Pat. No. 4,187,852 teaches a cross-linked insoluble elastomeric polypentapeptide which withdraws calcium ions from blood serum, so as to result is a calcifide peptide. Use as a matrix for replacing or repairing bone is disclosed.
U.S. Pat. No. 4,222,128 teaches a composite implant material (sintered apatite and a thermoplastic or thermosetting resin) the resultant composite moderately controls compatibility of the sintered apatite material to bone and improves the strength of the sintered apatite material.
U.S. Pat. No. 4,234,972 teaches a prosthesis for cement-free bonding comprising a metal substrate coated with a biologically active glass or glass-ceramic.
U.S. Pat. No. 4,277,238 discloses an artificial implantable bone-like graph material prepared from a decalcified and defattened bone piece or tooth taken from an animal or human. The implanted graft easily assimilates with existing tissues.
U.S. Pat. No. 4,294,753 teaches the use and preparation of a bone morphogenetic protein (BMP) or BMP/calcium phosphate coprecipitate for the treatment of bone defects caused by injury, malignancy, infection and congenital absence of bone.
U.S. Pat. No. 4,309,488 discloses an implantable bone replacement material comprising a matrix material consisting of a solid core of metal and a surface region of the metal having a fine-grained inclusion of calcium phosphate ceramic material.
U.S. Pat. No. 4,314,380 teaches the preparation of an artificial bone from which the organics have been removed, then it is butrned, baked and immersed in atelocollagen solution. The atelocollagen solution provides the artificial bone with good affinity with the neighboring bone tissue and allows for firm bonding to the neighboring tissue and bone cells. Moreover, it improves the strength of the artificial bone.
It is an object of the present invention to provide treatment of major bone deficiencies, such as non-unions without the use of electrostatic or electromagnetic electrical stimulation.
A further object of the invention is to promote treatment of large bone lesions without the use of autogenous bone transplantation.
A further object of the invention is to provide treatment of bone trauma sites without the use of autogenous bone transplantation where local soft tissues have been lost.
A further object of the invention is to provide a sterile composition that may be applied at surgical bone reconstruction by filling the bone lesion site.
A further object of the invention is to provide a sterile composition, which may be delivered to the lesion site by syringe.
A further object of the invention is to provide a composition which would minimize the invasion of fibrous or other tissue and maximize opportunity for bone formation.
A further object of the invention is to provide a composition which would promote vascularization of the three-dimensional space by preventing excessive packing of the inorganic phase.
A further object of the invention is to provide a composition which will hold the inorganic substances at the bone lesion site and thereby maintain anatomical dimensions.
A further object of the invention is to provide a composition which will provide for early force transfer in order to maintain the surrounding bone and give the additive mechanical conditions for preventing the loss of length and cross-section dimensions.
A further object of the invention is to provide a composition to promote the treatment of both simple and complex bone defects.
A further object of the invention is to provide a composition which does not require the need for immunosuppressive drugs.
A further object is to provide a composition which is easy to administer and also forms an intimate bond with the surrounding tissue.
A further object is to provide a composition which does not alter bone load characteristics thereby allowing sufficient load to the ingrowth and surrounding bone to prevent resorption.
A further object of the invention is to provide a composition which provides three-dimensional form stability where glutaraldehyde cross links exists within the hydrated collagen base material which is then mixed with HAP ceramic particulate or is cross-linked with the final composition form of the hydrated collagen base materials which coat the ceramic particulate.
It is a further object of the invention to provide a composition to promote the treatment of simple and complex bone defects where the presence of a viable periosteum is not necessarily present at the time of surgical placement.
The following has outlined some of the more pertinent objects of the present invention. These objects should be construed to be merely illustrative of some of the more pertinent features and applications of the invention. Many other beneficial results can be obtained by applying the disclosed invention in a different manner or modifying the invention within the scope of the invention. Accordingly, other objects and a fuller understanding of the invention may be had be referring to the summary of the invention and the detailed description describing the preferred embodiment in addition to the scope of the invention defined by the claims.